JP2019522024A - 経口送達と生物学的に同等である薬物動態を有する経皮送達システム - Google Patents
経口送達と生物学的に同等である薬物動態を有する経皮送達システム Download PDFInfo
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- JP2019522024A JP2019522024A JP2019503999A JP2019503999A JP2019522024A JP 2019522024 A JP2019522024 A JP 2019522024A JP 2019503999 A JP2019503999 A JP 2019503999A JP 2019503999 A JP2019503999 A JP 2019503999A JP 2019522024 A JP2019522024 A JP 2019522024A
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- Prior art keywords
- transdermal delivery
- delivery system
- therapeutic agent
- memantine
- donepezil
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Abstract
Description
本願は、米国仮出願第62/367,502号(2016年7月27日出願);米国仮出願第62/367,542号(2016年7月27日出願);米国仮出願第62/423,133号(2016年11月16日出願);米国仮出願第62/457,794号(2017年2月10日出願);米国仮出願第62/504,391号(2017年5月10日出願);および米国仮出願第62/504,408号(2017年5月10日出願)の利益を主張する。各々は、その全体が参照により本明細書中に援用される。
本明細書に記載される主題は、同程度の用量の治療剤の経口送達と生物学的に同等である薬物動態をもたらすように設計された、システムからの治療剤の経皮送達に関する。
皮膚を通じた治療活性剤の経皮送達は、その薬剤の血漿中レベルを持続的に一定に保つための手段を提供する。これは、経皮システムが皮膚上にある期間全体を通じて、血中レベルが一定であり続け、経口送達において見られる薬物濃度のピークおよびトラフを伴わない薬物の血中濃度がもたらされるという点で、経口投与を介した従来の療法とは異なる。経皮送達は、半減期が短い薬物に関して、かつ/または薬物を長半減期薬物(long half drugs)よりも早々に代謝してしまう可能性がある有意な肝臓の初回通過効果が存在する場合に利用される。
下に記載され例証される、以下の態様およびその実施形態は、例示的かつ例証的であることを意図したものであり、範囲に関して限定的なものではない。
I.定義
これより、以下において、様々な態様についてより完全に説明する。しかしながら、そのような態様は、多くの異なる形態で具体化することができ、本明細書に示される実施形態に限定されるものとして解釈されるべきではない;むしろ、これらの実施形態は、本開示が網羅的かつ完全であり、当業者にその範囲を完全に伝えることができるように提供されるものである。
対象に対して治療剤を経皮的に送達するための方法が提供される。複数の実施形態では、方法は、本明細書に記載される送達システムを使用する、1つまたは複数の中枢神経系(CNS)障害の処置を含む。本明細書に記載されるシステムおよび方法を使用して処置することができるCNS障害の例としては、限定されるものではないが、認知症(例えば、アルツハイマー病、パーキンソン病、ピック病、前頭側頭型認知症、血管性認知症、正常圧水頭症、ハンチントン病(HD)、および軽度認知障害(MCI))、神経関連状態、認知症関連状態、例えばてんかん、発作性障害、急性疼痛、慢性疼痛、慢性神経障害性疼痛が挙げられる。てんかん性の状態としては、複雑部分てんかん、単純部分てんかん、続発性全般てんかんを伴う部分てんかん、全般てんかん(欠神、大発作(強直間代性)、強直性、無緊張性、ミオクローヌス性、新生児、および点頭てんかんを含む)が挙げられる。追加的な特定のてんかん症候群は、若年性ミオクローヌスてんかん、レノックス・ガストー、内側側頭葉てんかん、夜間前頭葉てんかん、精神遅滞を伴う進行性てんかん、および進行性ミオクローヌスてんかんである。本明細書に記載されるシステムおよび方法はまた、脳血管性疾患、運動ニューロン疾患(例えば、筋萎縮性側索硬化症(ALS)、脊髄運動萎縮症、テイ・サックス病、サンドホフ病(Sandoff disease)、家族性痙性対麻痺)、神経変性疾患(例えば、家族性アルツハイマー病、プリオン関連疾患、小脳性運動失調症、フリードライヒ運動失調症、SCA、ウィルソン病、網膜色素変性症(RP)、ALS、副腎白質ジストロフィー、メンケス症候群(Menke's Sx)、皮質下梗塞を伴う常染色体優性脳動脈症(CADASIL);脊髄性筋萎縮症、家族性ALS、筋ジストロフィー、シャルコー・マリー・トゥース病、神経線維腫症、フォン・ヒッペル−リンダウ、脆弱X、痙性対麻痺(spastic paraplesia)、精神障害(例えば、パニック症候群、全般性不安障害、すべての型の恐怖症候群、躁病、躁うつ病、軽躁、単極性うつ病、うつ病、ストレス障害、外傷後ストレス障害(PTSD)、身体表現性障害、人格障害、精神病、および統合失調症)、および薬物依存(例えば、アルコール、精神刺激薬(例えば、クラック、コカイン、スピード、メタンフェタミン)、オピオイド、およびニコチン)、結節性硬化症、ならびにワールデンブルグ症候群(Wardenburg syndrome))、脳卒中(例えば、血栓性、塞栓症、血栓塞栓性、出血性(hemmorhagic)、静脈収縮性、および静脈性)、運動障害(例えば、パーキンソン病(PD)、ジストニア、良性本態性振戦、遅発性ジストニア、遅発性ジスキネジア、およびトゥーレット症候群)、失調性症候群、交感神経系の障害(例えば、シャイ・ドレーガー、オリーブ橋小脳変性症、線条体黒質変性、パーキンソン病(PD)、ハンチントン病(HD)、ギラン・バレー、カウザルギー、複合性局所性疼痛症候群I型およびII型、糖尿病性ニューロパチー、ならびにアルコール性ニューロパチー)、脳神経障害(例えば、三叉神経障害、三叉神経痛、メニエール症候群、舌咽神経痛(glossopharangela neuralgia)、嚥下障害、発声障害、および脳神経麻痺)、ミエロパチー(myelopethies)、外傷性脳および脊髄損傷、放射線脳損傷、多発性硬化症、髄膜炎後症候群、プリオン病、脊髄炎(myelities)、神経根炎、ニューロパチー(例えば、ギラン・バレー、タンパク異常血症と関連する糖尿病、トランスサイレチン誘発性ニューロパチー、HIVと関連するニューロパチー、ライム病と関連するニューロパチー、帯状疱疹と関連するニューロパチー、手根管症候群、足根管症候群、アミロイド誘発性ニューロパチー、らい性ニューロパチー、ベル麻痺、圧迫性ニューロパチー、サルコイドーシス誘発性ニューロパチー、多発性脳神経炎、重金属誘発性ニューロパチー、遷移金属誘発性ニューロパチー、薬物誘発性ニューロパチー)、軸索性脳傷害、脳症、ならびに慢性疲労症候群を含む障害によって引き起こされる疼痛の処置および予防にとっても有用である。本明細書に記載されるシステムおよび方法はまた、多発性硬化症、特に再発寛解型多発性硬化症の処置、ならびに多発性硬化症および/または再発寛解型多発性硬化症の再発の予防にとっても有用である。本明細書に記載されるシステムおよび方法によって、上の障害のすべてを処置することができる。
以下の実施例は、本質的に例証的なものであり、決して限定的であることを意図するものではない。
ドネペジル経皮送達システム
ドネペジルを含む経皮送達システムを、以下の通りに調製した。
ドネペジル経皮送達システムからのドネペジルのin vivo投与
ドネペジルを含む経皮送達システムを、実施例1に記載されているように調製した。12名のヒト対象を、経皮送達システムによって処置する群(n=6)または研究の1日目および7日目に服用される5mgのドネペジル(ARICPET(登録商標))の経口投与によって処置する群の2つに無作為化した。経皮送達システムは、皮膚に対して適用し、1週間着用させた後、取り外した。経皮送達システムで処置した対象からは、血液試料を毎日採取した。経口送達ドネペジルで処置した群では、血液試料を1日目および7日目に頻度の高い時間間隔で採取し、8、10、12、および14日目にも再度採取した。処置群におけるドネペジルの平均血漿中濃度を、図2A〜2Bに示す。
メマンチン経皮送達システム
メマンチンを含む経皮送達システムを、以下の通りに調製した。10グラム(g)のメマンチン塩基を、82.42gの酢酸エチル、4.34gのイソプロピルアルコール、12gのプロピレングリコール、および6.48gのレブリン酸の混合物に溶解して、透明な溶液を形成した。7.0gのヒュームドシリカ(AEROSIL(登録商標)200P)を添加し、混合物を均質化した。127.8gのアクリル酸/酢酸ビニルコポリマー(DURO−TAK(登録商標)387−2287、固形分含量50.5%)を添加し、混合物が均質になるまで混合した。
メマンチン経皮送達システムからのメマンチンのin vivo投与
メマンチンを含む経皮送達システムを、実施例3に記載されているように調製した。19名のヒト対象を、以下のうちの1つで処置される4つの群に無作為化した:(1)1週間着用される、メマンチン経皮送達システム(n=5);(2)3日間着用される、メマンチン経皮送達システム(n=7);(3)研究の1日目および7日目に服用される、28mgの経口投与メマンチン(NAMENDA XR(登録商標))。経皮送達システムを、皮膚に対して適用し、1週間(群1)または3日間(群2)着用させた後、取り外した。経皮送達システムで処置した対象からは、血液試料を毎日採取した。経口送達ドネペジルで処置した群では、血液試料を1日目および7日目に頻度の高い時間間隔で採取し、8、10、12、および14日目にも再度採取した。処置群におけるメマンチンの平均血漿中濃度を、図5A〜5Bに示す。
ドネペジル経皮送達システム
ドネペジルを含む経皮送達システムを、以下の通りに調製した。
ドネペジル経皮送達システム
ドネペジルを含む経皮送達システムを、以下の通りに調製した。
メマンチン経皮送達システム
薬物リザーバの調製:2.0gの量のグリセロールおよび2.0gのオクチルドデカノールを、29.35gの酢酸エチルおよび1.86gのイソプロピルアルコールの混合物と混合した。溶液中で、5.0gのメマンチン塩酸塩および1.95gの炭酸水素ナトリウムを、撹拌することによって分散させた。この分散体に対して、3.0gの架橋ポリビニルピロリドン(KOLLIDON(登録商標)CL−M)を添加し、均質化した。この均質化された分散体に対して、11.99gのアクリレートコポリマー(DURO−TAK(登録商標)387−2287、固形分含量50.5%)を添加し、よく混合した。この湿潤粘着剤配合物を剥離ライナー上にコーティングし、Werner Mathisコーターを使用することで乾燥させて、15mg/cm2の乾燥塗工重量を得た。
経皮システムを評価する方法
経皮送達システムを、実施例6に従って調製する。
経皮システムを評価する方法
経皮送達システムを、実施例5および6の教示に従って調製する。
Claims (29)
- 対象に対して治療剤を送達するための方法であって、
治療剤および前記治療剤を含むリザーバから構成される経皮送達システムを準備することであって、前記治療剤が、(i)経口的に送達された場合、約48時間を超える血中半減期を有し、(ii)慢性状態を処置するためのものである、準備すること、ならびに
対象の皮膚に対して前記経皮送達システムを投与することまたはそれを投与するように指示すること
を含み、
それによって、前記投与することが、前記治療剤の経口投与と生物学的に同等である、前記治療剤の定常状態での経皮送達を達成し、ここで、生物学的同等性は、(a)前記経皮送達システムから、および経口送達を介して投与される前記治療剤の、相対的な平均CmaxおよびAUCの90%信頼区間が、0.70から1.43の間にあること、または(b)前記経皮送達システムから、および経口送達を介して投与される前記治療剤の、AUCおよびCmaxの幾何平均比の90%信頼区間が、0.70から1.43の間にあることによって確立される、
方法。 - 前記治療剤が、難水溶性の薬剤である、請求項1に記載の方法。
- 生物学的同等性が、健常対象において確立される、請求項1または2に記載の方法。
- 生物学的同等性が、絶食状態において確立される、いずれかの先行する請求項に記載の方法。
- 生物学的同等性が確立され、生物学的同等性が、(a)前記経皮送達システムから、および経口送達を介して投与される前記治療剤の、相対的な平均CmaxおよびAUCの90%信頼区間が、0.80から1.25の間にあること、または(b)前記経皮送達システムから、および経口送達を介して投与される前記治療剤の、AUCおよびCmaxの幾何平均比の90%信頼区間が、0.80から1.25の間にあることによって確立される、いずれかの先行する請求項に記載の方法。
- 前記治療剤が、ドネペジル塩基、ドネペジル塩、メマンチン塩基、メマンチン塩、フィンゴリモド塩基、およびフィンゴリモド塩である、いずれかの先行する請求項に記載の方法。
- 前記慢性状態が、アルツハイマー病であるか、または前記慢性状態が、多発性硬化症である、いずれかの先行する請求項に記載の方法。
- 前記投与することまたは投与するように指示することが、週1回投与することまたは投与するように指示することを含む、いずれかの先行する請求項に記載の方法。
- 前記治療剤が、ドネペジル塩基またはドネペジル塩であり、前記経皮送達システムが、1〜25mg/24時間を提供する用量のドネペジル塩基またはドネペジル塩を含む、いずれかの先行する請求項に記載の方法。
- 前記経皮送達システムが、薬物リザーバおよび接触用粘着剤を含み、前記薬物リザーバおよび/または前記接触用粘着剤が、(i)グリセロール、(ii)クエン酸トリエチル、(iii)ポリビニルピロリドンのうちの1つを含む、いずれかの先行する請求項に記載の方法。
- 前記経皮送達システムが、薬物リザーバおよび接触用粘着剤を含み、前記薬物リザーバおよび/または前記接触用粘着剤が、(i)乳酸ラウリル、(ii)クエン酸トリエチル、および(iii)グリセロールのうちの1つを含む、請求項1から9のいずれか一項に記載の方法。
- 前記経皮送達システムが、(i)乳酸ラウリル、(ii)クエン酸トリエチル、および(iii)グリセロールのうちの2つを含む薬物リザーバを含む、請求項1から9のいずれか一項に記載の方法。
- 前記薬物リザーバが、ドネペジル塩酸塩および炭酸水素ナトリウムを含む、いずれかの先行する請求項に記載の方法。
- 前記薬物リザーバが、ソルビタンモノラウレートおよび乳酸ラウリルのうちの一方または両方を追加的に含む、請求項13に記載の方法。
- 前記治療剤が、メマンチン塩基またはメマンチン塩であり、前記経皮送達システムが、7〜28mg/24時間を提供する用量のメマンチン塩基またはメマンチン塩を含む、請求項1から5、7から8、または10から12のいずれか一項に記載の方法。
- 前記経皮送達システムが、薬物リザーバおよび接触用粘着剤を含み、前記薬物リザーバが、メマンチン塩およびアルカリ塩を含む、請求項1から5、7から8、または10から12のいずれか一項に記載の方法。
- 前記経皮送達システムが、オクチルドデカノールおよびグリセロールのうちの1つを含む薬物リザーバを含む、請求項15または請求項16に記載の方法。
- 前記メマンチン塩が、メマンチン塩酸塩であり、前記アルカリ塩が、炭酸水素ナトリウムまたは炭酸水素カリウムである、請求項16に記載の方法。
- 前記接触用粘着剤が、高級アルコールおよび生体適合性ポリマーを含む、請求項18に記載の方法。
- 前記高級アルコールが、ラウリルアルコール、イソステアリルアルコール、オクチルドデカノール、およびオレイルアルコールからなる群から選択される、請求項19に記載の方法。
- 前記生体適合性ポリマーが、ポリイソブチレン(PIB)、シリコーンポリマー、アクリレートコポリマー、ブチルゴム、ポリブチレン、スチレン−イソプレン−スチレンブロックコポリマー、スチレン−ブタジエン−スチレンブロックコポリマー、エチレン−酢酸ビニル(EVA)、それらの混合物、またはそれらのコポリマーからなる群から選択される、請求項19または請求項20に記載の方法。
- 前記薬物リザーバが、(a)約10〜30重量%のメマンチンHClと約5〜15重量%の炭酸水素ナトリウムとの反応によってin situで生成されるメマンチン塩基、(b)約5〜15重量%のオクチルドデカノール、(c)約5〜15重量%のグリセロール、(d)約10〜30重量%の架橋ポリビニルピロリドン、ならびに(e)約20〜50重量%のアクリレートポリマーから本質的になる、請求項15から21のいずれか一項に記載の方法。
- 前記治療剤が、フィンゴリモド塩基またはフィンゴリモド塩であり、前記経皮送達システムが、0.05〜2mg/24時間を提供する用量のフィンゴリモド塩基またはフィンゴリモド塩を含む、請求項1から5、7から8、または10から12のいずれか一項に記載の方法。
- 経皮システムを評価するための方法であって、
対象に対して、治療剤および前記治療剤から構成されるリザーバを含む経皮送達システムを投与することまたはそれを投与するように指示することであって、前記治療剤が、(i)経口的に送達された場合、約48時間を超える血中半減期を有し、(ii)慢性状態を処置するためのものである、投与することまたは投与するように指示すること、ならびに
対象に対して、経口投与を介して前記治療剤を投与することまたはそれを投与するように指示すること
を含み、
それによって、前記投与することが、前記治療剤の経口投与と生物学的に同等である、前記治療剤の定常状態での経皮送達を達成し、ここで、生物学的同等性は、(a)前記経皮送達システムから、および経口送達を介して投与される前記治療剤の、相対的な平均CmaxおよびAUCの90%信頼区間が、0.70から1.43の間にあること、または(b)前記経皮送達システムから、および経口送達を介して投与される前記治療剤の、AUCおよびCmaxの幾何平均比の90%信頼区間が、0.70から1.43の間にあることによって確立される、
方法。 - 前記経皮送達システムが、前記対象に対して、x mg/日の用量を投与し、経口投与を介して前記治療剤を投与される前記対象が、x mg/日の20%以内の用量を受容し、ここで、xは0.05〜25である、請求項24に記載の方法。
- 前記経皮送達システムが、前記対象に対して、x mg/日の用量を投与し、経口投与を介して前記治療剤を投与される前記対象が、x mg/日を受容し、ここで、xは0.05〜25である、請求項24に記載の方法。
- 前記経皮送達システムを投与される前記対象および経口投与を介して前記治療剤を投与される前記対象が、同じ対象である、請求項24に記載の方法。
- 前記経皮送達システムを投与される前記対象および経口投与を介して前記治療剤を投与される前記対象が、異なる対象である、請求項24に記載の方法。
- 生物学的同等性が、前記経皮送達システムを投与される前記対象から、および経口投与を介して前記治療剤を投与される前記対象から採取された血液試料から確立される、請求項24から28のいずれか一項に記載の方法。
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WO2018022814A1 (en) | 2018-02-01 |
AU2017302305A1 (en) | 2019-02-14 |
CA3031944A1 (en) | 2018-02-01 |
CN109789134A (zh) | 2019-05-21 |
US20180028467A1 (en) | 2018-02-01 |
US20180028461A1 (en) | 2018-02-01 |
US10016372B2 (en) | 2018-07-10 |
JP2024019737A (ja) | 2024-02-09 |
JP7469879B2 (ja) | 2024-04-17 |
JP2022060428A (ja) | 2022-04-14 |
US20230086303A1 (en) | 2023-03-23 |
EP3490559A1 (en) | 2019-06-05 |
KR102424270B1 (ko) | 2022-07-25 |
KR20190032461A (ko) | 2019-03-27 |
AU2023203613A1 (en) | 2023-07-06 |
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